Novel polymorphic forms of cipamfylline

ABSTRACT

This invention relates to novel crystalline H polymorphic forms, Form I, II and IV of Cipamfylline, methods of preparation, and use thereof in the treatment of PDE 4  and TNF mediated diseases. Cipamfylline is 1,3-di-cyclopropylmethyl-8-amino xanthine, and represented by formula (I).

FIELD OF THE INVENTION

[0001] This invention relates to novel crystalline polymorphic forms ofCipamfylline, and to methods for preparing them.

BACKGROUND OF THE INVENTION

[0002] The capacity to occur in different crystal structures is known aspolymorphism and is known to occur in many organic compounds. Thesedifferent crystalline forms are known as “polymorphic modifications” or“polymorphs” and are realized in their crystalline state. Whilepolymorphic modifications have the same chemical composition, theydiffer in packing, geometrical arrangement, and other descriptiveproperties of the crystalline solid state. As such, these modificationsmay have different solid-state physical properties such as shape, colordensity, hardness, deformability, stability, and dissolution properties,etc. Polymorphism of an organic drug molecule and its consequences willbe appreciated by the skilled artisan.

[0003] Cipamfylline, 1,3-di-cyclopropylmethyl-8-amino xanthine, has thechemical formula C₁₃H₁₇N₅O₂, m.w. of 275.31, and the followingstructural formula:

[0004] Its synthesis is described in Example 9, in Maschler et al.,Great Britain Patent Application No. 8906792.0 filed on Mar. 23, 1989,in its corresponding EPO patent EP 389282, and corresponding U.S. Pat.No. 5,734,051 whose disclosures are incorporated herein by reference intheir entirety.

[0005] Cipamfylline is a PDE₄ inhibitor and is useful in the treatment,including prophylaxis, of disease states mediated thereby.

[0006] Cipamfylline was also disclosed to have TNF inhibiting activityin Esser et al., PCT/US91/08734 (also published as EP 558659), and istherefore useful in the treatment, including prophylaxis of TNF mediateddisease states. Suitable assays, dosage forms, and dosage ranges, etc.for the polymorphs of this invention for use in the therapeutictreatment of diseases may be found in either the Maschler et al., or theEsser et al. patent applications whose disclosures are incorporatedherein by reference in their entirety.

SUMMARY OF THE INVENTION

[0007] This invention relates to a novel crystalline polymorph of the1,3-di-cyclopropylmethyl-8-amino xanthine, referred to hereinafter asForm I, which form of such compound is useful in the treatment of PDE₄or TNF mediated diseases.

[0008] This invention also relates to a novel crystalline polymorph ofthe 1,3-di-cyclopropylmethyl-8-amino xanthine, referred to hereinafteras Form II, which form of such compound is useful in the treatment ofPDE₄ or TNF mediated diseases.

[0009] This invention also relates to a novel crystalline polymorph ofthe 1,3-di-cyclopropylmethyl-8-amino xanthine, referred to hereinafteras Form IV, which form of such compound is useful in the treatment ofPDE₄ or TNF mediated diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a characteristic X-ray powder diffraction pattern forForm I. (Vertical axis: Intensity (CPS); Horizontal axis: DiffractionAngle, in Two Theta (degrees)).

[0011]FIG. 2 is a characteristic X-ray powder diffraction pattern forForm II. (Vertical axis: Intensity (CPS); Horizontal axis: DiffractionAngle, in Two Theta (degrees)).

[0012]FIG. 3 is a table showing the Torsion Angle Tabulations for FormsII and IV.

[0013]FIG. 4 is a Raman spectrum of Form I. (Vertical axis: Intensity;Lower horizontal axis: Wavenumber (cm<−1>)).

[0014]FIG. 5 is a Raman spectrum of Form II. (Vertical axis: Intensity;Lower horizontal axis: Wavenumber (cm<−1>)).

[0015]FIG. 6 is a Raman spectrum of Form IV. (Vertical axis: Intensity;Lower horizontal axis: Wavenumber (cm<−1>)).

[0016]FIG. 7 is a comparison of the Raman spectra of all three forms,Form I, II and IV, and the carbonyl stretching region of 1750-1600 cm⁻¹.(Vertical axis: Intensity; Lower horizontal axis: Wavenumber (cm<−1>)).

[0017]FIG. 8 is a comparison of the Raman spectra of all three forms,Form I, II and IV, and the region of 1000-800 cm⁻¹. (Vertical axis:Intensity; Lower horizontal axis: Wavenumber (cm<−1>)).

[0018]FIG. 9 is a comparison of the Raman spectra of all three forms,Form I, II and IV, and the region of 400-200 cm⁻¹. (Vertical axis:Intensity; Lower horizontal axis: Wavenumber (cm<−1>)).

[0019]FIG. 10 depicts the Form I molecule in three dimensions and with alabeling scheme.

[0020]FIG. 11 provides for a stereo drawing of the Form I molecule.

[0021]FIG. 12 shows a Table of Bond Distances in Angstroms for the FormI molecule.

[0022]FIG. 13 shows a Table of Bond Angles in Degrees for the Form Imolecule.

[0023]FIG. 14 shows a Table of Torsion Angles in Degrees for the Form Imolecule.

[0024]FIG. 15 shows a Table of Positional Parameters and Their EstimatedStandard Deviations for the Form I molecule. The x, y, and z fractionalcoordinates indicate the position of atoms relative to the origin of theunit cell, and B(A2) is the isotropic temperature factor.

[0025]FIG. 16 is a characteristic infrared absorption spectrum of asingle crystal of Form I.

[0026]FIG. 17 is a characteristic infrared absorption spectrum of asingle crystal of Form II.

[0027]FIG. 18 is a characteristic infrared absorption spectrum of asingle crystal of Form IV.

[0028]FIG. 19 is a comparison of characteristic infrared absorptionspectra of the single crystals of Forms I, II and IV.

[0029]FIG. 20 is a characteristic infrared absorption spectrum inpotassium bromide of Form I. (Vertical axis: Transmission (%); Lowerhorizontal axis: (Wavenumber (cm<−1>)).

[0030]FIG. 21 is a characteristic infrared absorption spectrum inpotassium bromide of Form II. (Vertical axis: Transmission (%); Lowerhorizontal axis: (Wavenumber (cm<−1>)).

[0031]FIG. 22 is a characteristic infrared absorption spectrum of acrushed crystal of Form I.

[0032]FIG. 23 is a characteristic infrared absorption spectrum of acrushed crystal of Form II.

[0033]FIG. 24 is a characteristic infrared absorption spectrum of acrushed crystal of Form IV.

[0034]FIG. 25 is a comparison of the infrared absorption spectra of asingle and crushed crystal of Form IV.

[0035]FIG. 26 depicts the Form IV molecule in three dimensions and witha labeling scheme.

[0036]FIG. 27 provides for a stereo drawing of the Form IV molecule.

[0037]FIG. 28 shows a Table of Bond Distances in Angstroms for the FormIV molecule.

[0038]FIG. 29 shows a Table of Bond Angles in Degrees for the Form IVmolecule.

[0039]FIG. 30 shows a Table of Torsion Angles in Degrees for the Form IVmolecule.

[0040]FIG. 31 shows a Table of Positional Parameters and Their EstimatedStandard Deviations for the Form IV molecule.

[0041]FIG. 32 depicts the Form II molecule in three dimensions and witha labeling scheme.

[0042]FIG. 33 shows a Table of Bond Distances in Angstroms for the FormII molecule.

[0043]FIG. 34 shows a Table of Bond Angles in Degrees for the Form IImolecule.

[0044]FIG. 35 shows a Table of Torsion Angles in Degrees for the Form IImolecule.

[0045]FIG. 36 shows a Table of Positional Parameters and Their EstimatedStandard Deviations for the Form II molecule.

DETAILED DESCRIPTION OF THE INVENTION

[0046] It has now been discovered that Cipamfylline can exist as any ofseveral novel crystalline forms, polymorphic forms, which differ fromeach other in their stability, physical properties, spectral data andmethods of preparation. Three of these novel polymorphic forms aredescribed in this application and are hereinafter referred to,respectively, as Form I, Form II, and Form IV.

[0047] Of the three novel polymorphs referred to above, Form I, exhibitsthe greatest stability. Form I is characterized by a minimum of fiveyears crystalline stability.

[0048] This invention also relates to a pharmaceutical compositioncomprising an effective amount of a polymorph of Form I with any of thecharacteristics noted herein, and a pharmaceutically acceptable carrieror diluent thereof.

[0049] This invention also relates to a pharmaceutical compositioncomprising an effective amount of a polymorph of Form II with any of thecharacteristics noted herein, and a pharmaceutically acceptable carrieror diluent thereof.

[0050] This invention also relates to a pharmaceutical compositioncomprising an effective amount of a polymorph of Form IV with any of theabove characteristics noted herein, and a pharmaceutically acceptablecarrier or diluent thereof This invention further relates to the use ofForm I for the treatment of a PDE₄ or TNF mediated disease in a mammalin need thereof, which method comprises administering to said mammal aneffective amount of a polymorph of Form I with any of thecharacteristics noted herein.

[0051] This invention further relates to the use of Form II for thetreatment of a PDE₄ or TNF mediated disease in a mammal in need thereof,which method comprises administering to said mammal an effective amountof a polymorph of Form II with any of the characteristics noted herein.

[0052] This invention further relates to the use of Form IV for thetreatment of a PDE₄ or TNF mediated disease in a mammal in need thereof,which method comprises administering to said mammal an effective amountof a polymorph of Form IV with any of the characteristics noted herein.

[0053] This invention results from a determination that certain batchesof Cipamfylline showed differences in their IR mull spectra. All batcheswere prepared by the same route with ethanol as the finalrecrystallization solvent therefore it appeared possible that speed ofcrystallization may affect crystal form. In the light of this,recrystallized samples were prepared by crash cooling a portion of thehot liquid while the remainder was allowed to stand and crystallizeunaided. In each case batch size was ca. 1 g or less. Samples were driedover silica gel under vacuum at room temperature. In thisrecrystallization program, three polymorphic forms have been positivelyidentified, and are described herein as Forms I, II and IV.

[0054] Therefore, this invention also relates to a method of preparing apolymorph of Form I with any of the above characteristics comprisingcrystallizing Cipamfylline in an alcoholic solution of ethanol (s/f),propanol(s/f), butanol(s/f), isopropanol(s/f), or an organic solvent ofethyl acetate(s/f), toluene*, or as a solvent, water*. Under certainconditions, tetrahydrofuran (s/f), and acetone (s) may also be used.

[0055] In additional work with fast cooling, i.e. an ice water bath foruse with smale scale samples, the time for the reaction temperature todrop from reflux to ambient takes approximately 1 minute with ethanol asa solvent.

[0056] In a prefered embodiment of this invention, 1-propanol is thesolvent of choice to prepare Form I polymorphic forms.

[0057] This invention also relates to a method of preparing a polymorphof Form II with any of the above characteristics comprisingcrystallizing Cipamfylline in an alcoholic solution of methanol(s/f), oran organic solvent of tetrahydrofuran (s), or acetone (f). Under certainconditions, chloroform* or pyridine* may be used.

[0058] This invention also relates to a method of preparing a polymorphof Form IV with any of the above characteristics comprisingcrystallizing Cipamfylline in an organic solvent of 50:50 mixture ofethanol and isopropanol.

[0059] *Due to the particularly low solubility of Cipamfylline insolvent marked with an asterix (*), such as toluene or water for Form I,the recrystallization procedure was modified, i.e. the hot solution wasfiltered to remove undissolved material and the filtrate was allowed tostand and crystallize out the compound.

[0060] The (s) term as used herein refers to slow, ambientrecrystallization. It is noted that the term “slow” cooling (and “fast”cooling) are relative terms. In this particular meaning slow cooling mayinvolve removal of the oil bath and air cooling. On the basis of scalealone (approximately 1 gm quantities for some experiments, versus acommerical batch size) cooling may actually be quite fast, such as inthe 15 to 30 minute range. However, under controlled circumstances, slowcooling is generally defined as approximately one (1) hour from refluxto ambient temperature. Very slow cooling will be approximately fromabout four (4) hours from reflux to ambient. Under these conditions FormII may also be obtained from ethanol as described later in thisdocument. However, similarly under the small batch sizes in some of theexperiments used for Form I, the ethanol (slow cooling) route is notnecessarily a reliable solvent/temperature of choice for Form I. It isalso noted that with regard to the use of acetone in fast cooling (i.e.use of an ice bath), Form I is formed. Limited analysis also indicatesthat use of acetone under the fast cooling route is not necessarily areliable solvent/temperature of choice for Form II.

[0061] The (f) term as used herein refers to fast, crash coolrecrystallization, such as by placing the flask in a ice water bath, orsimilar techniques for larger scale processing.

[0062] These three novel crystalline polymorphs of Cipamfylline, alsoreferred to as BRL 61063, all melt at about 305° C. to about 313° C.

[0063] The crystalline polymorph, Form I, exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks expressed dspacing (A) in decreasing intensity, at 12.302, 7.702, 8.532. 4.289, and2.854 as depicted in FIG. 1. A discussion of the theory of X-ray powderdetraction patterns can be found in Stout & Jensen, X-Ray StructureDetermination; A Practical Guide, Mac Millian Co., New York, N.Y.(1968).

[0064] The crystalline polymorph, Form II, exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks expressed dspacing (A) in decreasing intensity, at 12.001, 6.702, 3.687, 3.773, and7.345 as depicted in FIG. 2.

[0065] This invention also relates to the crystalline polymorph Forms I,II, and IV, of Cipamfylline that are further characterized by thecrystal parameters obtained from single crystal X-ray crystallographicanalysis as set forth in Tables 1, 2 and 3 below. The 3-D X-ray data wascollected at ambient temperatures. TABLE I Crystal Parameters of Form ICrystal Shape (mm): Flat needles Crystal Dimensions: 1.0 × 0.12 × 0.08mm Crystal Color: Colorless Space Group: P1 triclinic #2 Temperature:295 K Cell Constants: a = 10.829 (2)Å b = 12.636(2)Å c = 5.105(3)Å alpha(α) = 99.48(4) beta (β) = 91.53(4) gamma (γ) = 83.84(3) Volume: 685.0(8)Å³ Molecules/unit cell (Z)  4 ρ (calc), Density  1.354 g/cm⁻³ μ  7.362cm⁻¹ F(000) 292

[0066] TABLE II Crystal Parameters of Form II Crystal Shape (mm):Rectangular blocks Crystal Colour: Colorless Crystal Dimensions: 0.80 ×0.50 × 0.15 mm Space Group P2 _(l/c) monoclinic #14 Cell Constants a =12.227 (4)Å b = 7.448(2)Å c = 14.946 (8)Å alpha (α) = 90 (4) beta (β) =97.95(4) gamma (γ) = 90(4) Volume 1348.1(9) Å³ Molecules/unit cell (Z)  4 ρ (calc) Density   1.356 g/cm⁻³ μ   0.896 cm⁻¹ F(000)  584

[0067] TABLE III Crystal Parameters of Form IV Crystal Shape (mm) Flatneedles Crystal Color Colorless Crystal Dimensions 0.60 × 0.10 × 0.05 mmSpace Group P1 triclinic #2 Temperature 295 K Cell Constants a =10.210(3) Å b = 13.753(2) Å c = 4.942(31) Å alpha (α) = 97.94(2) beta(β) = 97.95(4) gamma (γ) = 83.33(2) Volume 677.1(5) Å³ Molecules/unitcell (Z)  2 ρ (calc) Density  1.350 g/cm⁻³ μ  7.448 cm⁻¹ F(000) 292

[0068] The unit cell dimension is defined by three parameters; length ofthe sides of the cell, relative angles of sides to each other and thevolume of the cell. The lengths of the sides of the unit cell aredefined by a, b and c. The relative angles of the cell sides are definedby alpha, beta, and gamma. The volume of the cell is defined as V. Amore detailed account of unit cells can be found in Chapter 3 of Stout &Jensen, X-Ray Structure Determination; A Practical Guide, Mac MillianCo., New York, N.Y. (1968).

[0069] The crystalline state of a compound can be unambiguouslydescribed by several crystallographic parameters: unit cell dimensions,space group, and atomic position of all atoms in the compound relativeto the origin of its unit cell. These parameters are experimentallydetermined by single crystal X-ray analysis. It is possible for acompound to form more than one type of crystal. These differentcrystalline forms are called polymorphs. It has now been discovered thatthere are three polymorphic forms of Cipamfylline. This discovery wasconfirmed by three separate single crystal X-ray analysis. A comparisonof the unit cell dimensions and space groups of these three crystallinestates are shown in Tables 1 to 3 above. Plotting the atomic positions,for the three polymorphs, of the atoms derived from the single crystalX-ray analysis confirms that the crystals contain Cipamfylline and noother molecules of crystallization or impurity.

[0070]FIG. 10 depicts the molecule in three dimensions and with alabeling scheme. FIG. 11 provides for a stereo drawing. Overall, themolecular conformation observed in Form I is identical to that of FormIV, with the exception of a clear disorder in one of the cyclopropylgroups (atoms C12 and C13), which was modeled with two positions ofequal occupancy for each of these atoms. The high degree of thermalmotion in the other cyclopropyl group (atoms C16 and C17) suggests thatit may be experiencing conformational flexing.

[0071] The unit cell of Form I crystals is of the same form as that ofForm III, with similar cell dimensions, a volume of 8 Å³ larger, andcorrespondingly, a density reduced by 0.15g cm⁻³. All of these effectsare in keeping with the presence of disorder in the channel which thecyclopropyl groups occupy.

[0072] Hydrogen bonding in this crystal structure is all intermolecularin nature and is similar, in terms of specific interactions to that seenin Form IV. As in the Form IV structure, the positions of the aminohydrogens are indicated from difference Fourier electron density maps.The position of H2N2 is not consistent with the participation of thathydrogen in a hydrogen bonding interaction. A distance of 3.399(3)Åbetween atoms N2 and O5 in Form I, however, suggest the possibility of aweak interaction analogous to that observed in Form II structure,although the distance observed in this form is longer by 0.4 Angstroms.When a position for H(2)N(2) was calculated which would satisfy thishydrogen bonding interaction, and attempts were made to refine it, thethermal value became unreasonable large, suggesting that the data do notsupport this alternative position. Thus the refinement was completedwith H2N2 in its original location as indicated by difference Fouriersynthesis. The associated metrical details of the other two hydrogenbond are: Summary of hydrogen-bonding of Form I H-bonding atomsAtom-atom distance Angle N(2) - - - N(1) 3.067(3) Å H(1)N(2) - - - N(1)2.16(3) Å 173(3)° N(3) - - - O(5) 2.793(3) Å HN(3) - - - O(5) 2.02(3) Å165(4)°

[0073] With regard to Form IV, FIG. 26 depicts the molecule in threedimensions and with a labeling scheme. FIG. 27 provides for a stereodrawing of Form IV. For the data described in this section, crystals ofForm IV were grown from a 50/50 mixture of ethanol and isopropanol byslow evaporation. Further, crystals of Form II were also grown from thissolvent mixture with Form II crystals appearing to nucleate first, withneedles of Form IV coming after the solution has evaporated for severaldays. Overall the molecular conformation observed in Form IV is verysimilar to that of Form II. Principal differences are concentrated inthe rotational orientation of the cyclopropyl groups which display anearly enantiomorphous relationship to their counterparts in the Form IIstructure, as summarized in the torsion angle tabulation Table 4, andshown in FIG. 3 herein.

[0074] Hydrogen bonding in the crystal structure for Form IV is allintermolecular in nature and is similar, in terms of specificinteractions to that seen in Form II. A major difference involves one ofthe two hydrogens on N2. There is a clear indication of the position forH1N2 in difference difference Fourier electron density maps. Theposition is not consistent with the participation of that hydrogen in ahydrogen bonding interaction. A distance of 3.273(3)Å between atoms N2and O5 in Form IV, however, suggest the possibility of a hydrogenbonding interaction analogous to that observed in Form II structure,although the distance observed in this form is longer by 0.2 Å. When aposition for H1N2 was calculated which would satisfy this hydrogenbonding interaction, and attempts were made to refine it, the thermalvalue became unreasonable large, suggesting that the data do not supportthis alternative position. Thus the refinement was completed with H1N2in its original location as indicated by difference Fourier synthesis.The associated metrical details of the other two hydrogen bond are:Summary of the hydrogen bonding of Form IV Atom-atom H-bonding atomsdistance Angle N(2) - - - N(1) 3.042(2) Å H(1)N(2) - - - N(1) 2.10(2) Å173(2)° N(3) - - - O(5) 2.731(2) Å HN(3) - - - O(5) 1.91(2) Å 160(2)°

[0075] With regard to Form II, FIG. 32 depicts the Form II molecule inthree dimensions and with a labeling scheme. The hydrogen bonding forthe crystal structure of polymorph Form II, is all intermolecular innature. The associated meterical details are: Summary of the hydrogenbonding of Form II Atom-atom H-bonding atoms distance Angle N2 - - - O53.049(3)Å Angle 151(2)° H1N2 - - - O5 2.26(3)Å N2 - - - N1 3.071(3)ÅAngle 137(3)° H2N2 - - - N1 2.41(3)Å N3 - - - O5 2.741(3)Å Angle 168(2)°HN3 - - - O5 1.90(3)Å

[0076] This structural information clearly shows that Forms I, II, andIV of Cipamfylline are all crystallographically different. The hydrogenbonding in all the forms is intermolecular in nature, and all threepossess hydrogen bonding between HN(2)—N(1) and HN(3)—(5).

[0077] Experimental Details:

[0078] Form I:

[0079] Flat needles were grown by slow evaporation from a mixture ofethyl acetate and butanol. Lattice parameters were determined from thesetting angles of 25 reflections well distributed in reciprocal spacemeasured on an Enraf Nonius CAD-4 diffractometer, and are furtherdescribed in Table 5 below. A full sphere of intensity data also werecollected on the diffractometer using graphite monochromated copperradiation from a rotating anode source and an ω-2θ variable speed scantechnique. Intensities of three monitor reflections measured at thebeginning, end and every two hours of exposure time changed by at most+/−0.1%. Three orientation controls also were monitored to assess anycrystal movement during the experiment. Data were corrected for Lorentzand polarization effects, and using the DIFABS algorithm, for theeffects of absorption. Redundant observations were averaged to obtainthe final data set.

[0080] The structure was solved by direct methods using the SHELXSprogram series. Atomic positions were initially refined with isotropictemperature factors and subsequently with anisotropic displacementparameters. The function minimized was Εw(|Fo|Fc|)². Weights, w, wereeventually assigned to the data as w=1/σ2 (fo)={σ²(Ic)+(0.04I)²].Positions for the hydrogen atoms attached to nitrogens were discoveredin subsequent difference Fourier maps. Positions for hydrogen atomsattached to carbons were calculated based on geometrical considerationsand held fixed in the fmal refinement stages along with isotropictemperature factors assigned 1.3(Beq) of the attached atom. Hydrogenatoms on the cyclopropyl groups were omitted from the refinement. Allother hydrogen positions were refined along with isotropic temperaturefactors. The full matrix least-squares refinement converged (maxΔ/σ=0.05) top values of the conventional crystallographic residualsR=0.056, wR=0.092. A final difference Fourier map was featureless withmaximum density of +/−0.285 eÅ⁻³. Values of the neutral atom scatteringfactors were taken from the International Tables for X-rayCrystallography. TABLE 5 Intensity Measurement Data for Form IDiffractometer: EnrafNonius CAD4 Radiation: CuKα λ = 1.5406ÅMonochromator: Graphite Single Crystal Scan Technique ω-2θ scan ScanSpeed: Variable 1.50 to 6.7 deg min⁻¹ in ω Background MeasurementsMoving crystal-moving counter at each end of the scan range; scantime/background time = 2.0 Range of Data:   2° ≦ 2θ ≦ 60°  −12 ≦ h ≦ 12 −14 ≦ k ≦ 14  −5 ≦ 1 ≦ 5 Standard Reflections: Three standards measuredevery three hours of x-ray exposure time Total No. Reflections; 23202032 unique Rint:   1.2% No. of Observed Data 1749 I>3 σ(I) No. ofVariables:  199 p:   0.04 R:   0.056% Rw:   0.092% Goodness of Fit:  3.311 Absorption Correction: 0.868 min 1.254 max 0.991 ave

[0081] The complete single crystal X-ray experimental data used toproduce the structure displayed in FIG. 10 for Form I is included inFIGS. 12 to 15. The parameters presented in the tables are measured inunits commonly used by those skilled in the art. A more detaileddiscussion of the units of measure can be found in International Tablesfor X-ray Crystallography, Vol. IV, pp. 55, 99, 149 Birmingham: KynochPress, 1974, and G. M. Sheldrick, SHELXTL. User Manual, NicoletInstrument Co., 1981.

[0082] Form II:

[0083] Rectangular plates were grown by slow evaporation from a solutionprepared in methanol/2-butanone. Lattice parameters were determined fromthe setting angles of 25 reflections well distributed in reciprocalspace measured on an Enraf Nonius CAD-4 diffractometer, and furtherdescribed in Table 6. Intensity data also were collected on thediffractometer using graphite monochromated molybdenum radiation and anω-2θ variable speed scan technique. A correction was applied to the datafor a 4.8% decrease in the intensities of three monitor reflectionsmeasured at the beginning, end and every two hours of exposure time.Three orientation controls also were monitored to assess any crystalmovement during the experiment. Data were corrected for Lorentz andpolarization effects, and using the DIFABS algorithm, for the effects ofabsorption. Symmetry equivalents and zonal reflections were averaged toobtain the final data set.

[0084] The structure was solved by direct methods using the MULTAN80program series. Atomic positions were initially refined with isotropictemperature factors and subsequently with anisotropic displacementparameters. The function minimized was Εw(|Fo|−|Fc|)². Weights, w, wereeventually assigned to the data as w=1/σ2 (fo)=[σ²(Ic)+(0.04I)2].Positions for the hydrogen atoms were discovered in subsequentdifference Fourier maps. The positions and isotropic temperature factorsfor amino hydrogen atoms and the methine hydrogens on the cyclopropylrings were allowed to refine. Positions for all other hydrogen atomswere calculated based on geometrical considerations and held fixed inthe final refinement stages along with isotropic temperature factorsassigned 1.3(Beq) of the attached atom. The full matrix least-squaresrefinement converged (max Δ/σ=0.005) to values of the conventionalcrystallographic residuals R=0.044, wR=0.054. A final difference Fouriermap was featureless with maximum density of +/−0.196 eÅ⁻³. Values of theneutral atom scattering factors were taken from the International Tablesfor X-ray Crystallography.

[0085] The complete single crystal X-ray experimental data used toproduce the structure displayed in FIG. 32 for Form II is included inFIGS. 33 to 36. The parameters presented in the tables are measured inunits commonly used by those skilled in the art. TABLE 6 IntensityMeasurement Data for Form II Diffractometer: EnrafNonius CAD4 Radiation:MoKaα λ = 0.71073Å Monochromator: Graphite Single Crystal Scan Techniqueω-2θ scan Scan Speed: Variable 2.50 to 6.7 deg min⁻¹ in ω BackgroundMeasurements Moving crystal-moving counter at each end of the scanrange; scan time/background time = 2.0 Range of Data:   2° ≦ 2θ ≦ 60°  0 ≦ h ≦ 14   0 ≦ k ≦ 8  −17 ≦ 1 ≦ 17 Standard Reflections: Threestandards measured every three hours of x-ray exposure time Total No.Reflections: 2469 2353 unique Rint:   3.4% No. of Observed Data: 1417 I>3 σ(I) No. of Variables:  202 p:   0.04 R:   0.044% Rw:   0.054%Goodness of Fit:   1.403 Extinction Coefficient: 7.869(1) × 10⁻⁷ DecayCorrection: 0.9769 min, 1.1374 max

[0086] Form IV:

[0087] Flat needles were grown by slow evaporation from a 50/50 mixtureof ethanol and isopropanol. Lattice parameters were determined from thesetting angles of 25 reflections well distributed in reciprocal spacemeasured on an Enraf Nonius CAD4 diffractometer, and further describedin Table 7. A full sphere of intensity data also were collected on thediffractometer using graphite monochromated copper radiation from arotating anode source and an ω-2θ variable speed scan technique.Intensities of three monitor reflections measured at the beginning, endand every two hours of exposure time changed by at most +/−1.1%. Threeorientation controls also were monitored to assess any crystal movementduring the experiment. Data were corrected for Lorentz and polarizationeffects, and using the DIFABS algorithm, for the effects of absorption.Symmetry equivalents and Friedel related mates were averaged to obtainthe final data set.

[0088] The structure was solved by direct methods using the SHELXSprogram series. Atomic positions were initially refined with isotropictemperature factors and subsequently with anisotropic displacementparameters. The function minimized was Εw(|Fo|−|Fc|)² . Weights, w, wereeventually assigned to the data as w=1/σ2 (fo)=[σ²(Ic)+(0.04I)²].Positions for the hydrogen atoms attached to nitrogens were discoveredin subsequent difference Fourier maps. Positions for hydrogen atomsattached to cyclopropyl methylene carbons were calculated based ongeometrical considerations and held fixed in the final refinement stagesalong with isotropic temperature factors assigned 1.3(Beq) of theattached atom. All other hydrogen positions were refined along withisotropic temperature factors. The full matrix least-squares refinementconverged (max Δ/σ=0.01) to values of the conventional crystallographicresiduals R=0.049, wR=0.071. A final difference Fourier map wasfeatureless with maximum density of +/−0.515 eÅ⁻³. Values of the neutralatom scattering factors were taken from the International Tables forX-ray Crystallography. TABLE 7 Intensity Measurement Data for Form IVDiffractometer: EnrafNonius CAD4 Radiation: CuKα λ = 1,5406ÅMonochromator: Graphite Single Crystal Scan Technique ω-2θ scan ScanSpeed: Variable 2.50 to 6.7 deg min⁻¹ in ω Background MeasurementsMoving crystal-moving counter at each end of the scan range; scantime/background time = 2.0 Range of Data:   2° ≦ 2θ ≦ 60°  −11 ≦ h ≦ 11 −15 ≦ k ≦ 15  −5 ≦ 1 ≦ 5 Standard Reflections: Three standards measuredevery three hours of x-ray exposure time Total No. Reflections; 39982017 unique Rint:   2.5% No. of Observed Data 1662 I> 3 σ(I) No. ofVariables:  202 p:   0.04 R:   0.049% Rw:   0.071% Goodness of Fit:  2.095 Extinction Coefficient: 1.411(1) × 10⁻⁶ Absorption Correction:0.911 min 1.088 max 0.997 ave

[0089] The complete single crystal X-ray experimental data used toproduce the structure displayed in FIG. 26 and 27, for Form IV isincluded in FIGS. 28 to 31. The parameters presented in the tables aremeasured in units commonly used by those skilled in the art.

[0090] The results of a single crystal X-ray analysis are limited to, asthe name implies, the one crystal placed in the X-ray beam.Crystallographic data on a large group of crystals provides powder X-raydiffraction. If the powder is a pure crystalline compound a simplepowder diagram is obtained. To compare the results of a single crystalanalysis and powder X-ray analysis a simple calculation can be doneconverting the single crystal data into a powder X-ray diagram, SHELXTLPlus (trademark) computer program, Reference Manual by SiemensAnalytical X-ray Instrument, Chapter 10, p. 179-181, 1990. Thisconversion is possible because the single crystal experiment routinelydetermines the unit cell dimensions, space group, and atomic positions.These parameters provide a basis to calculate a perfect powder pattern.Comparing this calculated powder pattern and the powder patternexperimentally obtained from a large collection of crystals will confirmif the results of the two techniques are the same.

[0091] X-Ray Powder Diffraction (XRD)

[0092] X-ray powder diffraction showed differences between all threeforms of polymorphs. Analysis on 4× Form I samples and 4× Form IIsamples showed that consistent matching diffraction patterns wereobtained for each set. This data is presented in FIGS. 1 and 2 herein.

[0093] Infrared Spectroscopy (IR)

[0094] The infrared absorption spectra has positively identified theexistence of Forms I, II and IV. This data is presented in FIGS. 16 to25 for compound, single crystal and crushed crystals of the variouspolymorphic forms.

[0095] In a compression and grinding study Form I was shown to be stableto compression and grinding, while Form II was shown to be stable tocompression but not to severe grinding.

[0096] Comparison of the IR spectra of Forms I and IV shows notabledifferences. The prominent band in a putative methylene deformationregion at 1430 cm⁻¹ (with a shoulder at 1442 cm⁻¹) for Form I is splitin Form IV to give a band at 1424 cm⁻¹ (with a shoulder at 1434 cm⁻¹)and a band at 1455 cm⁻¹ (with a shoulder at 1466 cm⁻¹). The carbonylstretching bands in Form I occur at 1648 (with a shoulder at 1656 cm⁻¹)and 1682 cm⁻¹, whereas Form IV they occur at 1656 cm⁻¹ and 1694 cm⁻¹.Weak features in the Form IV spectra at roughly 2000 and 2300 cm⁻¹ areabsent in Form I, but these may represent overtones from the carbonylregion.

[0097] These spectra were recorded using a Spectra-Tech Plan IImicroscope coupled to a P-E 1760 FTIR spectrometer (64-256 scans, ratiomode, MCT detector, 4 cm⁻¹ resolution, dry air purge). Spectra ofsamples without sample preparation were obtained by mounting crystals ona diamond window. Crushed crystals were prepared using a Spectra-Techmicro-Sample Plan (a compression cell) fitted with diamond windows. Astereo microscope was used to observe the behavior of the crystalsduring compression. After compression, the diamond windows wereseparated and a spectrum was recorded of the material adhering to one ofthe windows.

[0098] IR spectra of single crystals of Forms I, II and IV show numerousdifferences as well and are readily distinguishable. There aresignificant differences in relative band intensities between the IRspectra of single crystals of Forms I and II and the correspondingspectra obtained from potassium bromide discs; these differences occurthroughout the spectra, but are most obvious below 1700 cm⁻¹. Inparticular, note the difference in relative intensities of the bandsnear 1530, 1440, 1260, and 800 cm⁻¹ in the spectra of Form I, and thebands near 1540, 1420, 1260 and 1060 cm⁻¹ in the spectra of Form II.

[0099] The spectra of crushed crystals are very similar to thecorresponding KBr disc spectra. This is not surprising since bothcrushed crystals and KBr discs represent all molecular orientations. Inmany cases adequate IR transmission through crystalline samples can onlybe achieved by crushing.

[0100] There is poor correspondence between the single crystal andcrushed crystal spectra of Form IV, with the most marked differenceoccurring in the regions 1660-1620, 1260-1180, 1000-920, and 800-750cm⁻¹. However the crushed crystal spectra of Form IV are very similar tothe crushed crystal spectra of Form I. For these IR spectra, Form IVcrystals were obtained in the presence of those of form II, by slowevaporation form 50:50 ethanol: isopropanol and separated by hand.Conversion of Form IV to Form I is perhaps not surprising; threedimensional X-ray diffraction data indicates that molecular conformation(aside from orientation in the cyclopropyl groups) and hydrogen-bonding(in terms of specific interactions) are similar in Forms I and IV. Informs I and IV only one of the amino hydrogens is involved inhydrogen-bonding (this contrasts with Form II, in which all hydrogendonors were found to be involved). These findings relate well to theconclusions drawn from the single crystal infrared spectra of the threeforms, where the N-H stretching regions of Forms I and IV are similar,and different to Form II. Forms I and IV each have a band near 3455 cm⁻¹which is assigned to an unassociated NH function. In Form II this bandis absent and it is clear that all hydrogen donors are involved inhydrogen-bonding.

[0101] IR spectra of single crystals of Form IV have been recorded ondifferent instruments and are similar, except in the region of 1280-1260cm⁻¹. This can be explained by orientation effects. A definitive spectraof Form IV is presented herein as FIG. 18.

[0102] RAMAN Spectra

[0103] Raman Spectra for Forms I, II and IV are also shown herein asFIGS. 4 to 9. As can clearly be seen, significant differences existbetween the spectra of the three forms, allowing them to be readilydistinguished.

[0104] Form IV, under pressure has been shown under some circumstancesto convert to Form I, therefore, conventional sampling techniques, suchas alkali halide discs, or Nujol mull, may not be the best way to obtaininfrared spectra for this polymorph as the time involved in selectingappropriate sized crystals and obtaining a good quality spectra is high.

[0105] Raman spectroscopy provides for a quick method of distinguishingForms I, II and IV from each other without the need for samplepreparation.

[0106] Spectra were recorded using a Perkin-Elmer 2000 FT-Ramanspectrometer equipped with an Nd:YAG NIR laser (1.064 μm). The scanningconditions were 64-256 scans, quartz beamsplitter, 4 cm−1 resolution and1W laser power. The spectra of Form IV (FIG. 6) shows a significantamount of Raman scatter from the glass vial. This is seen as anunderlying cruve with a broad maximum near 400 cm−1. Glass makes only aminor contribution to the relatively intense spectra of Forms I and II(FIGS. 4 and 5).

[0107] The Raman spectra of Forms I, II and IV show numerous differencesand are readily distinguishable. The carbonyl stretching region,1750-1600 cm−1 (FIG. 7) shows the most marked difference between theforms (as was found to be the case with the IR spectra recorded fromsingle crystals (shown herein as FIGS. 16 to 18). Significant differenceexist between the three forms over the range of 1000-800 cm−1 (FIG. 8).The region 400-200 cm−1 (inaccessible when recording spectra using aninfrared microscope) also shows signficant differences (FIG. 9), thoughsensitivity in this region is relatively poor due to detector response.

[0108] Heats of Solution

[0109] Heats of solution were determined using acetone and methanol assuitable solvents. The endothermic values are given in Table 8 below.Different polymorphic forms give rise to different heats of solution.This is demonstrated by the data obtained herein. The value of H_(T),the heat of transition, is equal to the difference in crystal latticeenergy of the two forms and is the same in both solvents. This ispredicted since individual enthalpies are solvent dependent butdifference are not. From these results it suggests that dissolution ofForm II is more endothermic in both solvents and therefore the morestable form. Heats of solution for Form IV are in progress. TABLE 8Methanol Acetone Form (kcal/mol) (kcal/mol) 1 4.81 3.93 2 6.47 5.59 ΔH_(T) 1.66 1.66

[0110] Thermal Analysis

[0111] Differential Scanning Calorimetry (DSC) could not differentiatethe three forms of Cipamfylline. In each case thermograms showed meltingonly with similar onset and peak temperatures, typically T_(e)312,T_(p)314° C. However, when the heating rate was reduced sufficiently,the melting endotherm appeared as a fused melt, i.e. two componentsmelting. This behavior was common to both Forms I and II.

[0112] Thermomicroscopic observations showed that all three formssublime. The onset of sublimation was different for each form andcontinued over a wide temperature range (130-290° C. on a non-calibratedinstrument). This is not evident on the DSC thermograms. Meltingoccurred over a range (310-323° C. on a non-calibrated instrument) forall three forms: The possibility of two components melting consecutivelycould not be distinguished. The sublimate was collected for all threeforms and analyzed by IR and NMR. This showed that Form I had beenproduced.

[0113] Forms I, and II were annealed and were found to have converted toForm I by IR. The annealing procedure consisted of heating at 10° C./minfrom ambient to ca. 250° C. and holding at this point for ½-1 hour, thenallowing the sample to cool slowly to room temperature.

[0114] The above thermal experiments appear to indicate that Form I isthe most stable form. This could explain the similarity in meltingpoints of the three forms.

[0115] Synthetic Methods of Recrystallization:

[0116] Various batches of Cipamfylline were prepared by the same routeand the final recrystallization solvent and rate of cooling were variedas shown in Table 9 below. TABLE 9 Rate of Polymorph Solvent CoolingRecovery produced Ethanol slow 75% Form II Ethanol very slow 75% Form IIMethanol slow 70% Form II Acetone fast 22% Form I Tetrahydrofuran fast33% Forms I and III* Tetrahydrofuran slow 58% Form I

[0117] *In the case of THF (fast), it appears that the Form I producedis contaminated with another form, Form m. All data indicates that Formm could be a polymorph, but has not been characterised as it alwaysseems to be produced in mixtures. Slow cooling in this solvent producedForm I. Form II recrystallization:

[0118] Another experimental procedure used to recrystallize Form II froma solvent mixture of methanol/2-butanone as follows: Solid material froma cipamfylline sample was added to an aliquot of 2-butanone in a glassvial and warmed gently on a hot plate with stirring. Methanol was addeddrop-wise to the stirring warm solution until all solid materialappeared to have dissolved. Small holes were placed in the plastic vialcap and the clear, colorless solution was left to evaporate slowly in ahood at ambient temperature. Rectangular crystals of Form II appearedwithin 11 days.

[0119] In yet another study, Cipamfylline (1 g) was dissolved in EtOH(55 volumes) and cooled the solutions to 20-25° C. over 1 hour and 4hours respectively. The results are shown in Table 10 below. TABLE 10Recrystallisation of Cipamfylline from EtOH time to scale cool^(a) torecovered polymorphic^(b) Example (mmol) 20-25° C. (h) yield (%) form 13.6 1 74.9 II 2 3.6 4 75.2 II

[0120] In both cases, cooling over a prolonged period (≧1 h) gaveCipamfylline in polymorphic form II.

[0121] Form IV Recrystallization:

[0122] In another experimental procedure for recrystallization of FormIV, solid material from sample a Cipamfylline sample was added to analiquot of isopropanol in a glass vial and warmed gently on a hot platewith stirring. An equal volume of ethanol was added and stirringcontinued until all solid material appeared to have dissolved. Smallholes were placed in the plastic vial cap and the clear solution wasleft to evaporate slowly in a hood at ambient temperature. Over a shorttime rectangular crystals of Form II appeared followed in several daysby needles, one of which was used for the structure determination ofForm IV.

[0123] Form I Recrystallization:

[0124] In another experimental procedure for purification ofCipamfylline, (15.5 g) was dissolved in n-propanol (300 mL) at reflux.Cooling to room temperture lead to precipitation of a purified product,of Form I which was isolated by filtration and dried at 70° C.overnight. Wt. recovered Cipamfylline=11.96g; Yield=63%. Alternativesolvents, such as n-propanol/water, 3:1 also lead to similar yields andresults.

[0125] As noted above, 1-Propanol is a preferred solvent to prepareCipamfylline in polymorphic form I. The recrystallization procedure with1-propanol has been carried out on larger scale, approx. 2 kg scale withrepeated success. Cooling times from 97° C. to ambient temperature havevaried from about 70 minutes to overnight (approz. 8 to 12 hours). FormI has been formed reproducibly.

[0126] This process can be summarised below:

[0127] Crude BRL-61063 (2.06 kg) was dissolved in 1-propanol (40 L) atabout 97° C. The reaction was then cooled to about 18° C. over about 70minutes. The resulting suspension was filtered, the solid washed withprechilled 1-propanol (3×0.6 L) and dried in air at about 50° C.overnight to give purified Cipamfylline (1. 85 kg, 90%) Form I product.

[0128] In yet another recrystallisation study, similar to that shownabove in Table 9, again using MeOH, THF and acetone, the results arereported in Table 11 below. TABLE 11 Recrystallisation of Cipamfyllinefrom various solvents^(a) time to cool^(b) to recovered conc^(n) 20-25°C. yield polymorphic entry solvent (g/ml) (min) (%) ^(c)form 1 MeOH0.018 60 70 II 2 Acetone 0.004 40 64 II^(d) + I 3 Acetone 0.004 ˜1^(e)22 I 4 Acetone 0.004 ˜1^(e) 49 I 5 THF 0.017 ˜1^(e) 33 I + III 6 THF0.017 60 58 I

[0129] These data (Table 11) show that slow crystallisation of BRL-61063from MeOH (entry 1) provided product in polymorph form II. Polymorphfrom II was the predominant form obtained from slow cooling of anacetone solution of BRL-61063 (entry 2). Crash cooling of an identicalsolution (entry 3) gave BRL-61063 in exclusively form I. The fastcooling experiment was repeated and gave form I product (entry 4)confirming the original observation.

[0130] BRL-61063 was dissolved in THF and fast cooling led to isolationof material existing in polymorphic forms I and III (entry 5). Form Iwas exclusively obtained from slow cooling (entry 6).

[0131] These experiments therefore provide for another aspect of thepresent invention which is a process for producing Form I, which processcomprises placing crude Cipamfylline in an organic solvent, dissolvingthe crude product by heating to about reflux temperature and thencooling to crystalize out the desired form.

[0132] For Form I, the preferred solvent is 1-propanol, acetone of THF,more preferably 1-propanol. For Form I, the reaction cooling time isdetermined by the minimum time to cool from reflux, or from thetemperature at which dissolution of the crude product occurred in asolvent, i.e. from a minimum time to crash cooling a solution, which ona commerial scale is about 15 minutes. Preferably, the minimum coolingtime is a realistic time period of about 50-70 minutes to what ever isdesired, such as overnight (i.e. 8 to 12 hours). Preferably, the coolingtime is about 60-70 minutes with a range to about 120 minutes toovernight if desired. The cooling temperature is preferably from about0° C. to about 25° C., preferably from about 15° C. to about 25° C.,more preferably from about 18° C. to about 25 ° C. Also, ethanol is analternative solvent, but only if crash cooling is used. If Form II isdesired than ethanol, or methanol, is useful if a long cooling time isused 9 (see table 9 or 11).

[0133] If THF is used as a solvent to produce Form I, than slow coolingis necessary, and if acetone is used, than fast cooling is necessary aswell.

[0134] It is recognized that other combinations of solvents undersuitable conditions may be used herein, these combinations could includeadmixture with water, or with other organic solvents, such as DMF,heptanes, MeCN, n-butanol, isopropanol, ethyl acetate, TBME, toluene,decalin, etc. All of these are included within the meaning of amodifications or improvements of the specifically exemplifiedembodiments herein.

[0135] It is recognized that this is within the skilled artisans meansto produce the optimal solvent for use for recrystallization on alaboratory and commercial scale using the disclosures herein.

[0136] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0137] The above description fully discloses the invention includingpreferred embodiments thereof. Modifications and improvements of theembodiments specifically disclosed herein are within the scope of thefollowing claims. Without further elaboration, it is believed that oneskilled in the are can, using the preceding description, utilize thepresent invention to its fullest extent. Therefore the Examples hereinare to be construed as merely illustrative and not a limitation of thescope of the present invention in any way. The embodiments of theinvention in which an exclusive property or privilege is claimed aredefined as follows.

What is claimed is:
 1. A crystalline polymorph of1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an X-ray powderdiffraction pattern having characteristic peaks expressed in d spacing(A) in decreasing intensity, at approximately 12.302, 7.702, 8.532.4.289, and 2.854, and as expressed in FIG.
 1. 2. A crystalline polymorphof 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an infraredabsorption spectrum in potassium bromide having characteristicabsorption bands expressed in reciprocal centimeters as described inFIG.
 20. 3. A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-aminoxanthine that that exhibits a single crystal X-ray crystallographicanalysis with (a) crystal parameters that are approximately equal to thefollowing: Crystal shape (mm) Flat needles Crystal dimensions 1.0 × 0.12× 0.08 mm Crystal color Colorless Space Group P1 triclinic #2Temperature 295K Cell Constants a = 10.829 (2) Å b = 12.636 (2) Å c =5.105 (3) Å alpha (α) = 99.48 (4) beta (β) = 91.53 (4) gamma (γ) = 83.84(3) Volume 685.0 (8) Å³ Molecules/unit cell (Z) 4 Density, (ρ) g/cm⁻³1.354 μ 7.362 cm⁻¹ F (000) 292

the atomic positions of all atoms relative to the origin of the unitcell as represented in the tables of FIGS. 12 to
 15. 4. A crystallinepolymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits aRaman Spectroscopy pattern as expressed in FIG.
 4. 5. A crystallinepolymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits anX-ray powder diffraction pattern having characteristic peaks expressedin d spacing (A) in decreasing intensity, at approximately 12.001,6.702, 3.687, 3.773, and 7.345, and as expressed in FIG.
 2. 6. Acrystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine thatexhibits an infrared absorption spectrum in potassium bromide havingcharacteristic absorption bands expressed in reciprocal centimeters asdescribed in FIG.
 21. 7. A crystalline polymorph of1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a single crystalX-ray crystallographic analysis with crystal parameters that areapproximately equal to the following: Crystal Shape (mm): Rectangularblocks Space Group P2_(1/c) monoclinic #14 Cell Constants a = 12.227 (4)Å b = 7.448 (2) Å c = 14.946 (8) Å beta (β) = 97.95 (4) Volume 1348.1(9) Å³ Molecules/unit cell (Z) 4 ρ (calc) Density 1.356 g/cm⁻³ μ 0.896cm⁻¹ F (000) 584


8. A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthinethat exhibits a Raman Spectroscopy pattern as expressed in FIG.
 5. 9. Acrystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine thatexhibits an infrared absorption spectrum of a crystal havingcharacteristic absorption bands expressed in reciprocal centimeters asdescribed in FIGS. 18, 24 or
 25. 10. A crystalline polymorph of1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a single crystalX-ray crystallographic analysis with crystal parameters that areapproximately equal to the following: Crystal shape (mm) Flat needlesSpace Group P1 triclinic #2 Cell Constants a = 10.210 (3) Å b = 13.753(2) Å c = 4.942 (31) Å alpha (α) = 97.94 (2) beta (β) = 97.95 (4) gamma(γ) = 83.33 (2) Volume 677.1 (5) Å³ Molecules/unit cell (Z) 2 Density,g/cm⁻³ 1.350


11. A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthinethat exhibits a Raman Spectroscopy pattern as expressed in FIG.
 6. 12. Apharmaceutical composition comprising an amount of a polymorph accordingto any one of claims 1 to 4, and a pharmaceutically acceptable carrieror diluent.
 13. A pharmaceutical composition comprising an amount of apolymorph according to any one of claims 5 to 8, and a pharmaceuticallyacceptable carrier or diluent.
 14. A pharmaceutical compositioncomprising an amount of a polymorph according to any one of claims 9 to11, and a pharmaceutically acceptable carrier or diluent.
 15. A methodof treating a PDE₄ mediated disease in a mammal in need thereof, whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 1 to
 4. 16. A method oftreating a PDE₄ mediated disease in a mammal in need thereof, whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 5 to
 8. 17. A method oftreating a PDE₄ mediated disease in a mammal in need thereof whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 9 to
 11. 18. A method oftreating a TNF mediated disease in a mammal in need thereof, whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 1 to
 4. 19. A method oftreating a TNF mediated disease in a mammal in need thereof, whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 5 to
 8. 20. A method oftreating a TNF mediated disease in a mammal in need thereof, whichmethod comprises administering to said mammal an effective amount of apolymorph according to any one of claims 9 to
 11. 21. A process forproducing a crystalline polymorph of 1,3-di-cyclopropylmethyl-8-aminoxanthine, Form I, which process comprises a) dissolving1,3-di-cyclopropylmethyl-8-amino xanthine in 1-propanol; and b) coolingthe solution to crystalize out of solution the desired polymorphic FormI.
 22. The process according to claim 21 wherein the 1-propanol isadmixed with water.
 23. The process according to claim 21 wherein thecooling temperature is from about 0 to about 25° C.
 24. The processaccording to claim 23 wherein the crystalization time is from about 15to about 120 minutes.
 25. The process according to claim 21 wherein thexanthine is dissolved by heating the 1-propanol to reflux conditions.26. A process for producing a crystalline polymorph of1,3-di-cyclopropylmethyl-8-amino xanthine, Form I, which processcomprises a) dissolving 1,3-di-cyclopropylmethyl-8-amino xanthine intetrahydrofuran or acetone; and b) cooling the solution to crystalizeout of solution the desired polymorphic Form I.